The role of trigeminal nasal TRPM8-expressing afferent neurons in the antitussive effects of menthol

J Appl Physiol (1985). 2013 Jul 15;115(2):268-74. doi: 10.1152/japplphysiol.01144.2012. Epub 2013 May 2.

Abstract

The cold-sensitive cation channel TRPM8 is a target for menthol, which is used routinely as a cough suppressant and as an additive to tobacco and food products. Given that cold temperatures and menthol activate neurons through gating of TRPM8, it is unclear how menthol actively suppresses cough. In this study we describe the antitussive effects of (-)-menthol in conscious and anesthetized guinea pigs. In anesthetized guinea pigs, cough evoked by citric acid applied topically to the tracheal mucosa was suppressed by menthol only when it was selectively administered as vapors to the upper airways. Menthol applied topically to the tracheal mucosa prior to and during citric acid application or administered continuously as vapors or as an aerosol to the lower airways was without effect on cough. These actions of upper airway menthol treatment were mimicked by cold air delivered to the upper airways but not by (+)-menthol, the inactive isomer of menthol, or by the TRPM8/TRPA1 agonist icilin administered directly to the trachea. Subsequent molecular analyses confirmed the expression of TRPM8 in a subset of nasal trigeminal afferent neurons that do not coincidently express TRPA1 or TRPV1. We conclude that menthol suppresses cough evoked in the lower airways primarily through a reflex initiated from the nose.

Keywords: cough; turbinate; vagal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitussive Agents / pharmacology*
  • Cold Temperature / adverse effects
  • Cough / drug therapy
  • Cough / genetics
  • Cough / metabolism
  • Guinea Pigs
  • Male
  • Menthol / pharmacology*
  • Nasal Mucosa / metabolism
  • Neurons, Afferent / drug effects*
  • Neurons, Afferent / metabolism
  • Nose / drug effects
  • Nose / innervation*
  • Reflex / drug effects
  • Reflex / genetics
  • Respiration / drug effects
  • Respiration / genetics
  • TRPM Cation Channels / genetics*
  • TRPM Cation Channels / metabolism*
  • Trachea / drug effects
  • Trachea / innervation
  • Trachea / metabolism
  • Trigeminal Nerve / drug effects
  • Trigeminal Nerve / metabolism

Substances

  • Antitussive Agents
  • TRPM Cation Channels
  • Menthol